Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients.


Plain language summary
Sacubitril/valsartan is one of the newest guideline-recommended medications for patients with heart failure as it has shown reduction in hospitalizations and death. However, it has not been broadly adopted in clinical practice. Within an integrated health system in Southern California, we observed a rise in angiotensin receptor-neprilysin inhibitor (ARNI) use year-over-year to 7.48% by 2020. Patients given ARNI were younger with fewer comorbidities but had worse heart function. Racial minorities were equally likely to receive the medication compared with White patients.

Implications for managed care pharmacy
Wide-scale adoption of ARNI in practice has been gradual. Better understanding of the characteristics of the patients prescribed ARNI and potential barriers to its use may help further establish its place within goal-directed medical therapy for patients with heart failure.
Heart failure (HF) affects 6.2 million people in the United States, and its incidence is rising yearly. 1 It was reported on 379,800 or 13.4% of all death certificates in 2018 and had been estimated to cost the United States $30.7 billion in 2012. [1][2][3] Over the years, the discoveries of a short list of drugs have led to the development of precise algorithmic guidelines regarding guideline-directed medical therapy. 4 Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that inhibits the renin-angiotensin-aldosterone system and simultaneously inhibits the degradation of atrial and brain natriuretic peptide, thereby exerting multifaceted neurohormonal effects via vasodilation and natriuresis to afford additional cardiovascular benefits. 5 The benefits of ARNIs in patients with HF were first established in the Prospective Comparison of ARNIs with ACEIs to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial in 2014. ARNI use in HF was approved for clinical use by the US Food and Drug Administration (FDA) in 2015. 5 Since then, ARNIs have been recommended by the American College of Cardiology, American Heart Association, and Heart Failure Society of America, as well as the European Society of Cardiology guidelines as not only an alternative but also preferred over angiotensin coverting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). 4,6 Observations of ARNI use in the real-world setting have supported the cardiovascular benefits seen in clinical trials. [7][8][9][10][11][12] In 2020, the FDA granted an expanded indication for the use of ARNIs in some patients with HF with an ejection fraction (EF) greater than 40%, making it the first drug to be approved for this indication. 13 However, despite recommendations of ARNIs in HF guidelines and growing indications, wide-scale adoption of the drug into clinical practice appears to be low. 14,15 Potential factors preventing broad use of the medication include cost of the drug, the development of hypotension as a side effect, and the presence of only 1 large-scale randomized trial (PARADIGM-HF) to support its superiority over ACEIs or ARBs. 10,12,16,17 Notably, the PARADIGM-HF included 8,442 patients and showed a 20% reduction in cardiovascular mortality and HF hospitalization after being stopped early because of overwhelming benefit. 5 Knowledge on the actual penetrance of ARNIs in the real world is limited. 15 Better understanding of current ARNI use may help elucidate potential barriers to its use.
In this study, we sought to characterize ARNI use within a real-world setting and assess for any racial disparities among patients receiving ARNI.

STUDY DESIGN AND SETTING
We conducted a cross-sectional study within Kaiser Permanente Southern California (KPSC). KPSC is an integrated health system that provides care for more than 4.7 million members at 15 hospitals and greater than 200 medical offices, spanning across 10 counties  in Southern California. The KPSC membership population is sex-and gender-balanced and is also an ethnically, racially, and socioeconomically diverse representative of the Southern California population. 18 KPSC is a prepaid integrated health care plan, and members have equal access to health care services, benefits, clinic visits, and medications. This study was approved by the KPSC institutional review board and exempted from informed consent.

STUDY POPULATION
Adult patients (aged ≥ 18 years) with KPSC membership and a diagnosis of HF between January 1, 2014, and November 30, 2020, were first identified. A diagnosis of HF was defined by at least 2 different encounters with HF International Classification of Diseasaes (ICD) code (Supplementary Table 1, available in online article). The date of the first qualifying encounter was used as the index date to extract clinical information including laboratory, echocardiogram, and vital signs. We excluded patients who had a history of heart transplant or left ventricular assist device identified by ICD codes to avoid inclusion of patients with significantly different underlying characteristics. We further excluded patients who did not have pharmacy data or did not receive an ACEI, ARB, or ARNI. We restricted our cohort to only those receiving one of the above medications as we felt patients already receiving ACEIs or ARBs were the primary patients considered ARNI-eligible during our study period (Supplementary Figure 1). ACEI, ARB, or ARNI use was defined by a filled prescription and electronically abstracted by the corresponding generic product identifier code (Supplementary  Table 1). Finally, we excluded patients who had an EF greater than 40%. EF was defined by the most recent EF

STATISTICAL ANALYSIS
Prevalence of ARNI use was determined by the number of patients receiving ARNIs within the cohort across the entire observation window and within each year during the same period. Patients who received both an ARNI and ACEI (or ARB) within the study period (and each year) were counted as ARNI use. Characteristics of patients were presented descriptively by the use of ARNIs vs ACEIs/ARBs. Continuous variables were presented as median (interquartile range) and compared using the Kruskal-Wallis test. Categorical variables were presented as frequencies and percentages and compared using chi-square test. To evaluate for racial and ethnic differences in receiving ARNIs, we estimated odds ratio and 95% CI for receiving ARNIs for racial minorities by comparing each race and ethnicity with non-Hispanic White patients using multivariable logistic regression adjusting for other demographic variables. A 2-sided P value less than 0.05 was considered statistically significant. All statistical analysis were performed using SAS 9.4 (SAS Institute Inc.).

Results
Between 2014 and 2020, a total of 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs were identified ( Figure 1)

DATA ABSTRACTION AND VARIABLES OF INTEREST
KPSC has a comprehensive, integrated electronic health record and claims data system that allows for complete data capture both within and outside the system. All information on demographics, comorbidities, laboratory measurements, medications, device therapy, and HF hospitalization were extracted from the electronic health record and collected as part of routine clinical encounters.
Baseline demographics included age, sex, race and ethnicity, and body mass index. Race and ethnicity were based on self-report. Laboratory data included estimated glomerular filtration rate calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration equation. 19 Medical comorbidities included hypertension, diabetes, atrial fibrillation, compared with White patients and may reflect the equal access to care within our integrated health system. Nationally, the estimated proportion of patients with HFrEF prescribed ARNIs were 3.6% (1.5%-6.8%) for patients with Medicare plans and 13.7% (4.9%-31.8%) for patients with commercial plans in a cross-sectional study between August 2018 and July 2019. 14,15,20,21 Lower rates seen in the Medicare population may be because of the fact that this group is generally older with more comorbidities. We observed that ARNI-prescribed patients were a younger population. This may be attributed to tolerance of the drug. We observed the largest percentage increase in 2017 when ARNIs were officially adopted into HF guidelines and suspect ARNI use will continue to rise especially given a stronger recommendation in recent 2021 guidelines, particularly given the fact that ARNIs are recommeneded not only as an alternative but also as a preferred agent to replace ACEIs/ARBs in existing users. 4,22 Potential reasons for the slow adoption of ARNIs include the higher cost of ARNIs relative to ACEIs or ARBs and subsequent higher copays for patients, the fact that only 1 large randomized clinical trial demonstrated its superiority, and potential adverse drug-related outcomes including hypotension. 10,12,16,17,23 Some prescribers may feel that the findings of PARADIGM-HF are not as generalizable to the population they treat. Notably, our study population was generally older in age, included more males, and also included more Black patients compared with PARADIGM-HF trial participants. Symptomatic hypotension was seen both in the original clinical trial and following real-world studies and was the main side effect that led to discontinuation of the drug or inability to titrate to the maximum dose. 5,[7][8][9][10][11][12] Despite these current doubts and challenges, the benefits of ARNIs can be advantageous for patients with HF and health systems managing these patients. Furthermore, ARNIs now have an expanded FDA indication for use in some patients with HF with an EF greater than 40%, making it the first drug to be approved for this indication and applicable to all patients with HF.

Discussion
In a real-world clinical setting, 4.54% of patients with HFrEF receiving ACEIs, ARBs, or ARNIs between 2014 and 2020 received an ARNI. A rise in ARNI use was observed during the observation period. Patients receiving ARNIs had lower EF values and higher use of AICDs. Furthermore, patients receiving ARNIs tended to be younger, were more likely male, and had fewer comorbidities, which are findings that are consistent with previous observations from smaller populations from previous real-world studies. [7][8][9][10][11][12]14 Racial minorities were also no less likely to be prescribed an ARNI

LIMITATIONS
There are potential limitations to our study, which may confound the interpretation of our findings. Our study was cross-sectional in nature, which limited the interpretation of the temporal relationships between the variables studied and ARNI vs ACEI/ ARB use. We also relied on coding to identify HF as well as comorbidities, which can result in misclassification. Our EF value was defined by the most recent EF prior to index date, in which EF values may have changed or improved over time. In addition, we did not have specific information on economic burdens or other socioeconomic factors for our patient population. These factors, along with varying insurance plans that could result in higher copays, may have been a barrier to use for some patients. Finally, our findings from an integrated health system may not be generalizable to other care settings and patient populations given possibly greater variability in access and slower adoption of newer medications in nonintegrated health systems.

Conclusions
Among a diverse cohort of patients with HFrEF, ARNI use was low but comparable to existing reports and has risen through the years. Patients receiving ARNIs were younger with fewer comorbidities, while having lower EF. Patients from racial minority groups were no less likely to receive ARNI compared with White patients.